Aim
In line with current recommendations [7, 8], the primary aim of this protocol article is to
describe the design of a randomized controlled clinical trial investigating the effects of motivational nondirective resonance breathing (MNRB) and transcutaneous vagus nerve stimulation (tVNS) on photoplethysmography (PPG) measured heart rate variability (HRV) in patients diagnosed with FM. Secondary outcomes are changes in self report numeric rating scale (NRS) pain intensity, pain detection threshold (PDT), pain tolerance threshold (PTT), and pressure-pain limit (PPL) determined by computerized cuff-pressure algometry (CPA), blood pressure (BP) as well as health related quality of life. The principal objective is to explore the following four research questions:
- Does a standardized sham-controlled tVNS intervention and/or MNRB intervention have effects upon PPG- measured HRV?
- Is a substantial change in HRV associated with a significant change of self-report NRS pain intensity?
- Is a substantial change in HRV associated with a change in computerized cuff pressure algometry PDT, PTT, and/or PPL?
- Are there changes in BP following either an active or sham tVNS intervention and/or a MNRB intervention?
- Are there effects on health related quality of life and behavior following either an active or sham tVNS intervention and/or a MNRB intervention?
Design
This study will use a single-blind randomized controlled experimental design which will be
reported according to the CONSORT statement [9] and the Guidelines for Reporting Articles on Psychiatry and Heart rate variability (GRAPH) [10] in order to expedite translational research efforts, improve research methods, replication, and peer-review [11] (Table 3). A total of N=112 consenting FM patients will be consecutively recruited and randomized from the Department of Pain Management and Research at Oslo University Hospital, Ullevål, in Oslo, Norway, during the Summer and Fall of 2019. Participants will be randomized to either an experimental tVNS group, a sham tVNS group, an experimental MNRB group, or a sham MNRB group. Both active and sham treatment interventions will be delivered at home, twice a day, for 15 min in the morning and for 15 min in the evening, for a total duration of 2 weeks (14 days). Treatment adherence to both interventions will be monitored electronically through a portable Android device and from a Daily Treatment Journal. An 80 % completion of tVNS stimulation and MNRB training (a completion of 23 treatment sessions out of a total 28) will be regarded as adequate adherence in this project. Participants are invited to the clinic twice for pre- and post-intervention data collection. An overview of the participant selection, study design, and study flow is illustrated in Figure 1.
Covariates
Sociodemographic characteristics included which can have a significant impact upon HRV include age [12], sex [13], body mass index (BMI), waist-to-hip ratio (WHR), physical activity levels [14], usual sleeping habits and hours slept prior to clinical visitation, meal consumption within two hours prior to clinical visitation, oral contraceptive use for women, habitual levels of alcohol [15], nicotine [16], and caffeine intake. Cardiovascular diseases [17], psychophysiological disorders such as depression and anxiety [18], as well as various cardioactive medications have a considerable impact upon HRV and pain and will be accounted for. In addition, antidepressant classes (e.g., tricyclics) [19], some antipsychotic classes (e.g., clozapine) [20], benzodiazepines [21], antihypertensives [22], some types of statins, as well as some prescription pain medication use may significantly effect HRV and will be recorded. Non-prescription pain medication as well as sleep aids will also be documented.
Inclusion criteria
Participants must be between the ages of 18 and 65 with an average NRS of 6 - 10 [23] and must have a confirmatory diagnosis of chronic widespread pain (CWP), including fibromyalgia (FM), (Read Code: MG30.01) as defined in the ICD-11 [24]. CWP is currently defined by the American College of Rheumatology 2010/2011 criteria to be a fundamental feature of FM, defined as pain lasting ≥ 3 months, located axially, above and below the waist, and on both sides of the body with physical symptoms that include fatigue and waking unrefreshed [25]. This study will use the 2016 revision to the 2010/2011 FM diagnostic criteria [26] which introduces important changes based on experience both within clinical and research settings. A participant included in this study must satisfy the following 3 conditions:
- Widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score ≥ 5 OR WPI of 4–6 and SSS score ≥
- Generalized pain, defined as pain in at least 4 of 5 regions, must be present. Jaw, chest, and abdominal pain are not included in generalized pain
- Symptoms have been generally present for at least 3
- A diagnosis of fibromyalgia is valid irrespective of other A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses [26].
Exclusion criteria
Participants must not have any past history and/or presence of comorbid severe neurological or psychiatric disorders (e.g., mania, psychosis, suicidality, bipolar/schizophrenia/autism spectrum disorders) [10] and/or neurodegenerative disorders (e.g., Parkinson´s, Alzheimer´s, Huntington´s disease). Participants will be further excluded on pregnancy or planned pregnancy [27]; planned surgery; receiving treatment for any type of eating disorder (e.g., obesity, anorexia nervosa, etc.) [28]; head trauma; migraine; active heart implants (e.g., pacemaker) [29]; and active ear implants (e.g., cochlear implant). Individuals who have practiced meditation consistently (for more than 20 min/day) within the last six months will also be excluded [30].
Enrolment procedure
Study and contact information will be posted and updated regularly on the Oslo University Hospital website, ClinicalTrials.gov, CRISITN (Current Research Information System In Norway), and various social media platforms. After reading about the study, interested participants are instructed to log in to Nettskjema— a secure digital data management and collection system in Norway— and fill out a brief digital inclusion/exclusion form consisting of exclusion criteria, diagnostic criterion for FM, and an NRS scale. If participants meet self-reported inclusion criteria, they will be contacted by testing administrators with an invitation to participate and an appointment day and time for both Clinical Visitation I (CVI) and Clinical Visitation II (CVII) at the Department of Pain Management and Research, Oslo University Hospital.
Upon arrival at the Department for CVI, participants are provided with an informed consent. At this time, participants will have the opportunity to ask any of the testing administrators questions about the study and their contribution. Once the informed consent is signed, participants will be formally enrolled into the study.
Data management
This study will use Viedoc— an electronic data capture web-based solution used for clinical trial data collection and management that complies with all relevant health regulations [31] and the FDA Code of Federal Regulations 21 Part 11. The Clinical Trial Unit at Oslo University Hospital will perform the setup and design of our Viedoc electronic case report form (eCRF) and audit the study flow throughout the trial period. Testing administrators will actively use Viedoc for all participant data entry throughout the entirety of the study. Signature of the testing administrator is reacquired to ensure the completeness and accuracy of the participant data that has been obtained in the eCRF.
Data omissions and/or corrections in Viedoc will be justified and accounted for within the eCRFs. After the database is locked, the investigator (C.E.P.) will receive a digital copy of the subject data for archiving at the investigation site. The data will be securely stored at the research site database at Oslo University Hospital. Data will be de-identified so that each study participant is only recognizable by his/her unique Viedoc trial subject number. The data will be stored 5 years for further analyses and voluntary follow-up 6 months, 1 year, and 3 year after study closure.
Randomization and blinding procedure
Randomization
The computer-generated randomized allocation sequencer will be imported into the Viedoc eCRF system and made available to testing administrators. Only testing administrators will have access to participant treatment allocation and the allocation will not be available until the participant has signed the informed consent and deemed eligible to participate in the study.
This investigation will use a list randomization recruitment method [32] for CV I where participants will be randomly allocated to receive one of the four treatment groups: tVNS #1 (active); tVNS #2 (sham); MNRB #1 (active); MNRB #2 (sham). The randomization will be stratified by sex (Male = 1, Female = 2) and cardioactive medications (Yes = 1, No = 0) with varying block size within strata. Viedoc will generate the randomization number as well as the allocated treatment group for each participant.
Participants will be considered as taking cardioactive medication if they report that they are currently taking any medication for high BP, cholesterol, heart disease, or prescription pain medication. Participants will also be considered as taking cardioactive medication if they answer that they use tranquilizers, antidepressants, and/or antipsychotics either “less than every week”, “every week, but not daily”, or “daily”. Participants are permitted to continue taking any previously prescribed pain medications/psychopharmacological treatments that are necessary during the trial period.
Blinding
Active and sham treatment allocation is concealed from the participants and testing administrators. Both testing administrators and study participants will be told that they will provide/ receive two different versions of nerve stimulation at different locations on the ear (for the tVNS group) or that there are two breathing techniques that are being explored (for the MNRB group) in this investigation [33]. The testing administrators will introduce either “Version 1” (Active) or “Version 2” (Sham) of the treatment interventions.
The principal investigators (C.E.P. and H.B.J.) are blinded to patient treatment allocation as well as the randomization form in Viedoc. This form will only be visible to the testing administrators performing participant data collection. To protect against export of blinded data during the study, there will be two export roles in this study: (1) Blinded export and (2) Unblinded export. Blinded data export role will be given to the investigators prior to database lock while the Unblinded data export role will be given to the investigators only after database lock.
Statistical considerations and sample size calculation
An independent trial statistician who is blinded to the treatment allocation will complete the initial analysis for the main outcomes. Data analyses will be performed using IBM SPSS version 25, R software, and SAS® software after importing data from Viedoc. To sufficiently detect a difference between groups in HRV as it relates to NRS pain intensity, a sample size between 30 and 77 (depending on the HRV metric used) is typically needed [34]. However, subgroups are commonly employed within designs that have been suggested to require 20 participants per cell [35]. Furthermore, researchers have typically used Cohen’s calculations of small (0.2), medium (0.5), and large (0.8) effect sizes when quantifying the magnitude of group differences for HRV investigations. However, it has been recommended that these guidelines should only be used when the effect size distribution (ESD) is unknown; analyses have shown that Cohen’s guidelines underestimate the magnitude of small and large effect sizes and that HRV studies are generally underpowered [36]. A change on the NRS of 20% as our secondary outcome measure in this study for participants between CV I and II will be considered to be a clinically significant treatment efficacy [37, 38].
Due to our power calculation and in light of these findings, effect sizes of 0.25, 0.5, and 0.9 should be interpreted as small, medium, and large effects (after rounding to the closest 0.05). To achieve a statistical power of 0.8 to detect a large effect size, 21 participants are required per group in a case-control study [36]. However, in order to account for possible participant dropout, 28 participants per group will be included which correlates to a statistical power of 0.9. This recommended sample size which is based upon the aforementioned ESD can be tailored to our specific study used to appropriately power this research investigation [36]. This makes it more likely to better replicate and derive true effect size estimates. Mean with standard deviation or median with interquartile will be reported for continuous variables/data. Frequency and percentage will be given for categorical variables/data.
Missing data will be treated as follows: If the first (morning pre-intervention) NRS/HRV recording is missing, the last (evening post-intervention) NRS/HRV recording will be used from the night before. If the second (morning post- intervention) NRS/HRV recording is missing, then the first (morning pre-intervention) NRS/HRV recording will be used. If the third (evening pre-intervention) NRS/HRV recording is missing, then the first (morning pre- intervention) NRS/HRV recording will be used. Finally, if the last (evening post-intervention) NRS/HRV recording is missing, then the third (evening pre-intervention) NRS/HRV recording will be used. If all morning and evening NRS/HRV recordings are missing from a day, then NRS/HRV recordings from the day before will be used based upon the assumption that improvement/change is not present.
Baseline characteristics as mean with standard deviation or median with interquartile and frequency with percentage will be described for the four participant groups, active and sham. The change from the first to second data points will be calculated for the 14-day treatment session in regards to HRV and NRS present pain intensity. The change from CVI to CVII HRV, NRS present pain intensity, and NRS average pain intensity will be determined. Difference in changes between the groups in the morning session and evening session will be examined and tested by using two-way analysis of variance (ANOVAs) or random intercept and slope models. For overall difference in the changes between the four groups regardless of morning, evening or days, random intercept models or repeated one-way analysis of variance (ANOVAs) will be used to analyze the data. The tests will be two-sided, and the significance level will be set to 0.05.
Description of intervention arms
- Motivational Nondirective Resonance Breathing™ (MNRB™)
MNRB™ is a meditation-based deep breathing intervention developed by the lead author (CEP) [39] which is based on emergent findings in integrative neuroscience and autonomic self-regulation in cardiopulmonology.
Participants will perform MNRB™ at home for 15 minutes [40] in the morning upon waking and 15 minutes at night before going to bed (preferably at the same time for each individual participant) for a total duration of 2 weeks. Participants will use the BarTek™ device in order to practice MNRB™. The BarTek™ device is a CE-approved respiratory gating device compatible with an Android smartphone. Krüger&Matz Flow 5 Android smartphones will be used for running and recording the MNRB™ program with the BarTek™ respiratory gating device when practicing either active or sham MNRB™. Participants will receive MNRB™ user training at CV I and be provided with a BarTek™ operational worksheet which they will follow every morning and evening when practicing MNRB™.
- Active MNRB™ will be practiced relaxed, sitting back in a chair no more than 30 degrees from the horizontal, with both feet flat on the floor, hands on thighs with palms facing downward. Participants are further instructed to not talk or make any movements during their treatment session. The BarTek™ respiratory gating device is placed upon the diaphragm— around the abdomen, below the rib cage, and an inch (about two finger widths) above the navel. Participants open the MNRB™ program on the Krüger&Matz Flow 5 Android phone, which is connected wirelessly via Bluetooth to the BarTek™ respiratory gating device, and are guided through a 15 minute MNRB™ breathing intervention which guides participants from an average respiration rate of 12 breadths/min to a resonance frequency rate of 6 breadths/min— the most optimal means of increasing cardiac- vagal tone (HRV) via respiration [29]. Out of a full (100%) breathing cycle, participants are instructed to use the stomach to breathe in to full inspiratory capacity for 30% and exhale for 60% by tightening and pulling the stomach back toward the spine. At the end of each inspiration and expiration, participants are instructed to retain their breadth for 5% of the cycle [41]. The participant is instructed to allow the chest to remain immobile throughout the entirety of the session [42, 43]. This is achieved through a feedback system actively engaging the patient to follow a orb that indicates stages of breathing and constantly correcting participants when they While practicing, participants are to engage in a nondirective state of mind [44], where a relaxed focus of attention is established by listening to the inspiration and expiration sound guides of the MNRB™ program. Attention is neither directed toward staying with the respiration sound guides nor directed toward observing the spontaneous flow of thoughts and sensations [44]. Sensations, such as pain, during MNRB™ are accepted without actively directing attention toward them or away from them [39].
- Sham MNRB™ is practiced relaxed, sitting back in a chair no more than 30 degrees from the horizontal, with both feet flat on the floor, hands on thighs with palms facing upward. Participants are instructed not to talk or make any movements during their treatment session. Participants will be instructed to breathe at the normal respiration rate for an adult (12 breadths/ min) [45] by following a respiratory pacer [46] on the Krüger&Matz Flow 5 Android MNRB™ program while counting their breadth [33]. Out of a full (100%) breathing cycle, participants are instructed to breathe normally with a 49% inhale and a 49% exhale without any (i.e. 1%) breath retention at the end of each inspiration and expiration. Participants are instructed to maintain a focused attention on their breath while actively detecting mind wandering [47].
Transcutaneous Vagus Nerve Stimulation (tVNS)
The tVNS device (“Nemos®”; cerbomed GmbH, Erlangen, Germany) (Figure 5) stimulates the afferent auricular branch of the vagus nerve located medial of the tragus at the entry of the acoustic meatus [48]. This device has received CE approval as indication that it complies with essential health and safety requirements [49]. The ear is first cleaned with an alcohol wipe and the electrode is sprayed with a conductive fluid to ensure optimal stimulation. Two titan electrodes mounted on a gel frame are connected to the Nemos® pocket-size stimulator and placed in the concha of the left ear in order to avoid stimulation of fibers to the heart. Stimulation intensity is individually adjusted (from 0.1 mA to 10 mA) with a pulse width of 250 µs and a consistent stimulation frequency of 25 Hz for optimal stimulation [50]. During CV I, participants will familiarize themselves with the stimulation device and its proper usage under the guidance of the testing administrator. During this visitation, the intensity of the tVNS will be slowly increased until the optimal intensity (mA) is reached (i.e., a slightly uncomfortable tingling sensation) for each individual participant [33]. Both active and sham stimulation constantly alternate between active stimulation for 30 s, followed by a break of 30s [108]. Participants will perform active or sham tVNS at home for 15 minutes [40] in the morning upon waking and 15 minutes at night before going to bed (preferably at the same time for each individual participant) for a total duration of 2 weeks. Due to habitation, participants will be allowed to readjust this stimulation intensity during their 2 week intervention period if needed.
- Active tVNS is performed in a relaxed position, sitting back in a chair no more than 30 degrees from the horizontal, with both feet flat on the floor, and hands on thighs with palms facing downward. The bipolar stimulation electrode is placed correctly within the concha of the left Participants are instructed to breathe normally while not talking or making any movements during their session.
- Sham tVNS is performed in a relaxed position, sitting back in a chair no more than 30 degrees from the horizontal, with both feet flat on the floor, and hands on thighs with palms facing upward. The bipolar stimulation electrode is turned 180° and placed incorrectly over the center of the left earlobe instead of the outer auditory canal [51]. This area is known to be free of cutaneous vagal innervation [52] and produces no activation in the cortex and brain stem [51]. Participants are instructed to breathe normally while not talking or making any movements during their
Data acquisition
Testing administrators input data directly into Viedoc on a Windows 7 HP EliteDesk 800 G2 SFF desktop computer located in the clinical visitation room at the Department of Pain Management and Research, Oslo University Hospital, Ullevål. Height is recorded with a Seca 206 (Seca GmbH, Hamburg, Germany) device which is bolted into the wall and leveled. Weight is obtained using an ADE M320000 (ADE Germany GmbH, Hamburg, Germany) digital electronic floor scale. Waist and hip circumferences are recorded with a MyoTape (AccuFitness, LLC, Greenwood Village, U.S.A.) and BP is taken utilizing a Philips IntelliVue MMS X2 (Philips Medizin Systeme GmbH, Hamburg, Germany) multi measurement module and transport monitor.
- CameraHRV
Photoplethysmography (PPG)-measured HRV data will be obtained from CameraHRV (Marco Altini, Amsterdam, Netherlands)— an Android App which has been utilized in multiple clinical trials [53, 54, 55] and validated with both the Polar H7 device and the golden standard electrocardiography (ECG) [56]. PPG- measured HRV is a reliable means of computing HRV [57] and will be used to assess heart rate as well as time-based (AVNN, SDNN, rMSSD, pNN50) and frequency-based (LF, HF) resting HRV. Krüger&Matz Flow 5 Android smartphones without SIM card and telecommunication capability will be used to run CameraHRV and record HRV for both the clinical visitations and the patient daily readings. HRV values will be computed via the reflection through the illumination of the skin of a participant’s right index finger using the Krüger&Matz Flow 5 camera´s flash. CameraHRV detects the amount of light that is reflected by the camera located next to the light source [58] (see Table 1 for signal processing).
This study will use resting HRV recordings of 1 minute. Reducing the HRV recording window to a duration of 1 min, in comparison to the standardized 5 min recording, is acceptable when rMSSD is considered as the primary HRV parameter of interest [59]. A 1 min recording of the natural log of rMSSD (lnRMSSD) has also been proven to offer good reliability in comparison to the classical 5 min recording of rMSSD [60]. Furthermore, high-frequency HRV (hfHRV) also shows reasonable agreement between ultrashort-term recording windows (60 s or less) and 5-min periods [60, 61]. Several studies use hfHRV as an index of vagal tone [29] due to its strong correlation with rMSSD [62, 63]. However, unlike hfHRV, rMSSD has been shown to be insusceptible to confounding respiratory effects during the recording window [10, 61]. In addition to the main analysis performed with one ideal variable reflecting vagal tone (RMSSD), it is recommended [29] that researchers perform the same analyses with the other variables depicting vagal tone (hfHRV, SDNN, and pNN50). Date and time of day for every HRV recording will be saved within the CameraHRV program which can be used as a proxy for treatment compliancy for all participants during their 2-week home treatment.
- BarTek™ (Figure 6)
The BarTek™ respiratory gating device (VRMind, Wroclaw, Poland) designed for practicing MNRB™ measures abdominal expansion via strap tension that is induced by the diaphragm during the entire respiratory cycle. The elastic strap of the BarTek™ sensor is placed around the waist of each participant and is adjusted in length in order to produce a minimal resistance to respiratory movement. Tension measurement is implemented by a strain gauge circuit. This circuit contains a strain gauge measurement element, and a temperature compensation element. High precision measurement is ensured by using a high resolution analog digital converter. Device output signal has an electric potential difference that is sampled at 80 Hz. The signal is transmitted to the Krüger&Matz Flow 5 Android smartphone via a Bluetooth Low Energy protocol. Date and time of day along with all respiratory information will be recorded and saved within the MNRB™ program. The raw signal processing used in order to obtain each participants´ respiration dynamics (e.g. rate and volume) is shown in Table 2.
- DoloCuff
Computerized cuff-pressure algometry (CPA) will be administered using the DoloCuff device with software version 2.0.5.1 (DoloCuff; Unique Electronic Aps, Hvidovre, Denmark) in order to assess clinical pain sensitivity mechanisms in FM patients. The DoloCuff CPA consists of a double chambered 13 cm-wide textile high-pressure 13.5 cm x 76 cm tourniquet cuff (VBM Medizintechnik GmbH, Sulz, Germany), a computer-controlled air compressor (Unique Electronic Alps), a 10-cm electronic visual analog scale (VAS), and a stop-button for immediate release of air in the tourniquet cuff. The tourniquet is tightly mounted around the widest part of the m. gastrocnemius in order ensure reliable pressure readings.
Ramp inflation of 1 kPa/s [64] will be used in order to record a participant´s pain detection threshold (PDT), pain tolerance threshold (PTT), pressure-pain limit (PPL), and stop time [65]. Cuff PDT is defined as the pressure value the first time the VAS score exceeds 0 (i.e. at the moment of transition from a sensation of strong pressure to first sensation of pain) whereas cuff PTT is defined as the pressure value when the participant terminates the pressure inflation (i.e. when the pain due to the pressure of the cuff becomes intolerable) [65]. A maximum pressure of 150 kPa and a maximum time under pressure of 180s are set as the upper limits throughout the study [66]. The maximum pain intensity (VAS-peak) and time to VAS-peak will be extracted along with the individual slopes in pain intensity rise and fall from the start of cuff inflation to the end of cuff inflation. Areas under the VAS-curve are also calculated based on raw data [67].
- ViedocMe
Participant reported outcome measures (PROMs) in the form of questionnaires (see below) will be completed electronically using the ViedocMe functionality available in Viedoc at CV I and II. Study staff will create a ViedocMe account for each participant in the participant’s Clinic View in Viedoc and provide an unique log-in profile (user name, pin-code, and ViedocMe web-address) for each participant. Participants are to use this information to log in to their personal ViedocMe account on a tablet (Samsung Galaxy Tab A6 32GB) which is connected to Oslo University Hospital´s secure wireless account. The questionnaires in ViedocMe will only be available for completion the day of each clinic visitation. Participants will complete the questionnaires at the end of each visitation. After the time- window has expired (i.e. at midnight on the day of the clinic visit), questionnaires can no longer be completed electronically. If problems arise using ViedocMe, or if the participant prefers to use paper forms, paper copies of the questionnaires will be handed out to the participant and the data will be entered into Viedoc by testing administrators. Questionnaires are only available to participants in Norwegian. For a list of names with descriptions of each questionnaire utilized in this study see the Appendix.
List of questionnaires in the order of their completion:
- Credibility Expectancy Questionnaire
- Participant Global Impression of Change
- EQ-5D-5L
- Hopkins Symptom Checklist
- Multidimensional Assessment of Interoceptive Awareness, version 2
- Spiritual and Religious Attitudes in Dealing with Illness
- Pain Catastrophizing Scale
- Brief Pain Inventory
- Insomnia Sleep Inventory
- Oswestry Low Back Pain Disability Questionnaire
- General Health Questionnaires
- Daily Treatment Journal
Participants will receive a take-home Daily Treatment Journal where they will record their treatment session day, time (morning or evening), pre- and post- treatment HRV recording (Yes/ No), as well as pre- and post- treatment NRS pain intensity. Participants will also be instructed to write any thoughts, feelings, and/or reflections in regards to their overall treatment experience. Upon completion of the 2-week treatment, participants will hand their Daily Treatment Journal to the assigned research administrator at CV II where it will be recorded directly into Viedoc